Desmopressin, 1-(3-mercaptopropionic acid)-8-D-arginine-vasopressin (hereinafter also abbreviated as "DDAVP") is an analog of the neurohypophyseal peptide vasopressin. DDAVP is indicated in the management of a variety of medical conditions such as irregular urination or diurea, particularly those associated with diabetes insipidus and nocturnal enuresis.
DDAVP is currently available as an aqueous nasal spray composition which is administered by means of a metered spray pump. For instance, MINIRIN.RTM. nasal spray, Ferring AB, Sweden, contains 10 .mu.g of desmopressin acetate per 100 .mu.l, 0.5% of chlorobutanol (w/v) as preservative, and sodium chloride. Intranasal administration of about 200 .mu.l MINIRIN.RTM. spray, containing about 20 .mu.g of desmopressin, provides an antidiuretic effect lasting in most adult patients for about 8 to 12 hours. In a minority of cases a dose of up to 40 .mu.g (400 .mu.l) is required for similar effects.
For most nasally administered agents, the capacity of the human nasal cavity surface for holding aqueous solutions is limited. In most adults, this capacity is about 400 .mu.l. For efficient systemic absorption of nasally administered therapeutics, the vehicle carrying the drug must remain in contact with the mucus-lined epithelium for a sufficient period of time.
400 .mu.l volume is close to the maximum useful volume for known nasal spray compositions containing desmopressin. Nasal spray compositions having low concentrations of DDAVP might allow coverage of a wider range of patients, such as including very young or elderly patients. However, even such dilute concentrations must be delivered in minute doses because of the potency of DDAVP. On the other hand, about 100 .mu.l (containing a dose of 10 .mu.g) of known solutions containing DDAVP is the lowest dose volume that can be conveniently reproduced by single actuations of the metered spray pump, and remain therapeutically effective.
Harris et al., J. Pharm. Sci. 77 (1988) 337-339, conducting experiments based on healthy human volunteers, state that a given amount of desmopressin in larger volume, when given in a single dose, is absorbed substantially less effectively than the same amount in a smaller volume (see FIG. 1, Harris, ibid.). These findings are in full agreement with those of Anik et al., J. Pharm. Sci. 73 (1984) 684-685, who conducted similar tests on rhesus monkeys with nasally administered solutions containing the decapeptide nafarelin acetate. Both reports favor higher concentrations and discourage use of more dilute solutions.
The known results obtained with desmopressin are based on analysis of plasma levels of desmopressin and factor VIII:C. The release into plasma of factor VIII:C is known to be stimulated by high doses of desmopressin. The dosage administered intranasally in such experiments was approximately 300 .mu.g, about ten times the average dose given to patients with urinary disorders.
Thus, there exists a problem in the art for achieving a balance between therapeutic needs and dosage related problems of DDAVP nasal compositions. There is a need in the art for precisely metered, easily administered, and consistently reproducible nasal delivery compositions containing DDAVP.